Editorial

Caffeine, a type of methylxanthine, is the most widely used central nervous system stimulant through consumption of coffee, tea, chocolate, and many brands of beverages and energy drinks. The average amount of caffeine consumed in the U.S. population has remained constant at approximately 300 mg per person per day [1]. On the cellular level, caffeine interferes with multiple signaling pathways. It acts as an antagonist of all four types (A1, A2A, A2B, and A3) of adenosine receptors. It competitively inhibits phosphodiesterases (PDEs). Furthermore, it activates intracellular Ca2+ channel ryanodine receptors (RyRs) to release Ca2+ from the endoplasmic reticulum [2]. In addition to the psychoactive effects of enhancing alertness and alleviating fatigue, caffeine also has physiological effects on other systems of the body, as seen in a number of recent studies discussed below.

The circadian clock of the body is a primary regulator of the sleep-wake cycle. It is measured by the rhythmic concentrations of the hormone melatonin in the body fluid. A study published on the September 16 issue of Science Translational Medicine by Burke et al. [3] showed caffeine consumption (200mg, the equivalent of a double espresso) 3 hours before bedtime combined with dim-light, compared to dim-light alone, induced a ~40 min delay of the human circadian rhythm as measured in melatonin secretion in vivo [3]. They also used human osteosarcoma U2OS cells to study the cellular mechanism since U2OS cells express the key signaling molecules in circadian rhythms such as A1 adenosine receptor (A1R), PDEs, and RyRs. Chronic application of caffeine lengthened the circadian period of molecular oscillations in vitro in U2OS cells. Two other drugs, CGS-15943 and IBMX, were used for their effects on adenosine receptors and PDEs respectively. The authors found caffeine applied effects synergistically with increasing doses of IBMX, but not with CGS-15943, suggesting the action of caffeine on the circadian clock regulation is dependent on adenosine receptors, but not on PDE. Knockdown of the gene ADORA1 coding for A1R using siRNA caused an attenuation of caffeine's effect on lengthening the cellular circadian period. This modifying effect of caffeine on the circadian clock may explain the widespread sleep problems and other problems associated with disturbed sleep in populations that heavily consume caffeinated beverages.

Many athletes favor energy drinks containing caffeine in hopes of enhancing endurance as well as short-term, high-intensity physical performance. Early studies have attributed caffeine's performance enhancing effect to reduced pain perception in the central nervous system during exercise [4,5]. A recent study, published on the May 13 issue of Scientific Reports by Behrens et al. [6] now linked caffeine to the modulation of muscle strength and activation [6]. The study showed that caffeine ingestion (oral intake 8 mg/kg in a gelatin capsule) induced an acute increase of voluntary muscle strength one hour after the intake. This increase of muscle strength was due to the increased voluntary activation of the quadriceps muscle during isometric (17%), concentric (17%) and eccentric contractions (27.6%), instead of changes of spinal reflex responses.

With or without the taste of coffee, caffeine apparently affects autonomic arousal, respiratory response, and reported alertness. A study published on the September issue of Psychopharmacology by Benke et al. [7] studied the subjects’ physiology parameters and startle eye blink responses after giving subjects caffeine either with the expectation of arousal induction when mixed in coffee, or without the expectation when mixed in bitter lemon soda [7]. Regardless if it was offered in coffee or bitter lemon soda, caffeine (4 mg per kg body weight) increased skin conductance level, decreased heart rate, increased minute ventilation, decreased end-tidal CO2, and increased reported alertness. Interestingly, the results of behavioral tests in this study suggest both caffeine ingestion and the expectation of arousal (coffee consumption) contribute to the startle eye blink reflex magnitude.

Caffeine, when given in combination with noise, may make hearing impairments even worse. Mujica-Mota et al. [8] studied the effect of caffeine on hearing impairments following acoustic trauma [8]. Guinea pigs were exposed to noise (6 kHz at 120 dB for one hour) combined with intraperitoneal caffeine (120 mg/kg/day for 14 days). These animals showed greater impairment in hearing measured by auditory brainstem responses. In addition, diminished number of spiral ganglion cells was observed together with weight loss and higher alertness. Caffeine did not cause damage in the digestive system, liver, nor the auditory hair cells. This study was published on American Journal of Otolaryngology.